1. Field of the Invention
This invention relates to controlled release dosage forms and to methods of designing such dosage forms and methods of manufacturing such dosage forms, and more particularly a controlled release dosage form manufactured by three-dimensional printing.
2. Description of the Related Art
There are at least two physical mechanisms that can be important in controlled release drug delivery: erosion and diffusion.
Diffusion involves the passage of interior contents of a dosage form out through the surface of the dosage form while the surface is not removed, or, more generally, it involves motion of contents within the dosage form. It is governed by concentration gradients and diffusivities.
As an example of diffusion-controlled dosage forms, oral dosage forms have been fabricated conventionally such as by tablet pressing, and then have been coated with a release barrier coating. The coating has been permeable to water and gastric fluids, while not being soluble in these liquids. Ingestion of the dosage form by the patient has resulted in water penetrating the film and beginning dissolution of the Active Pharmaceutical Ingredient (API) inside the tablet. The dissolved form of the API has then been able to diffuse through the film material. The natural release profile of a dosage form governed by diffusion is that the cumulative amount of API released is proportional to the square root of time since initiation of release, i.e., Q=k*t0.5. The release rate of such a dosage form is the derivative of this function, namely: r=k′*t−0.5, which is a release rate that decreases with time.
The other release mechanism, erosion, involves the physical removal of material from the surface of a dosage form, such as by its dissolution in bodily fluids or by its degradation by bodily fluids. Release of API occurs because of this removal of material from the dosage form. Erosion-controlled dosage forms, when made with uniform composition throughout, have had a release rate that is proportional to the instantaneous surface area of the dosage form. Therefore, as the dosage form has become smaller, the release rate has also decreased.
Another controlled release dosage form has been a device known as an osmotic pump. Such devices have been constructed from a core containing the API, a selectively impermeable coating with a defined exit orifice, and a hygroscopic salt or other material that swells when wet and squeezes the API out through the orifice. This type of dosage form has suffered from the need for an exact size orifice and the need for the film to be defect free other than at the defined exit orifice.
An erodible dosage form made by three-dimensional printing, which has included geometric design and compositional variation in the interior of the dosage form, has been described in U.S. Pat. No. 6,280,771. The dosage form of that patent has provided bursts or phases of API release but did not teach a method or dosage form for providing zero-order release of API.
Various APIs work best with specific release profiles that are optimum for that particular API. One commonly required release profile is zero-order release, which is a release rate of API that is constant with respect to time. Such a release profile is desirable in cases where the API must be delivered to the patient's body at a constant rate in order to maintain constant or nearly constant concentration of API in the blood to maintain therapeutic effectiveness. This is particularly useful for APIs with short half-lives in the patient's bloodstream. A zero-order controlled release dosage form can maintain constant concentration of API in a patient's bloodstream with fewer doses administered to the patient than would be necessary with conventional burst release dosage forms, and this could improve patient compliance.
Other APIs may require an escalating release profile, wherein the release rate starts off relatively low and then increases over the course of the release. Escalating release may be desirable for APIs where the patient develops a tolerance over the course of medication. An example of this type of API is nitrates for treating angina. Another type of API for which escalating release would be helpful is H-2 inhibitors, because they are absorbed by the body more easily in the upper portion of the gastrointestinal tract than in the lower portion.
Other APIs may require a decreasing release profile, wherein the release rate starts off relatively high and then decreases over the course of the release. Decreasing release may be appropriate for APIs where an initial high dose is desirable followed by slower release. An example of this type of treatment would be APIs for arthritis, where initially a high blood level of API is needed to eliminate morning pain and stiffness, followed by lower levels to keep the patient pain-free during the day.
True zero-order release has been difficult to obtain with traditional dosage forms. For erosion-based dosage forms, the surface area has become smaller as time progressed, and thus the API release rate has become slower as the release progressed. For diffusion-based dosage forms, the surface area has been essentially constant, but the API inside the dosage form has not been available in infinite supply, and therefore the driving force for diffusion of API out of the dosage form has decreased as the release progressed because the concentration of API within the dosage form decreased. For both types of processes, the usual tendency has been for release rate to decrease as time progressed.
Researchers have claimed zero-order release from other geometries and dosage forms. Langer (Annals of Biomedical Engineering (1995) 23. QD.1 01-111) has achieved zero-order release in surface-erodible thin slabs of uniform API distribution. Ker{hacek over (c)} (Proceed. Int'l Symp. Control. Rel. Bioact., Mater., Controlled Release Society. Inc., (1998) 25 pp. 912-913) has approximated zero-order release using a three phase dosage form in which the different phases degraded at different rates. A device has recently been invented by Odidi (OROS™ technology, Alza Corp., http://www.alza.com), which features an osmotic “push-pull” mechanism as a means to achieve zero-order release. Yet another method of delivering an API in an approximately zero-order release has been a method wherein the dosage form uses a swellable cylindrical central core covered with insoluble caps that cover the axial faces of the tablet, but not the circumference. When ingested by the patient, the core of the tablet has swelled over time, maintaining a constant tablet surface area for release, leading to zero-order release.
In general, all of these designs attempting to produce zero-order release have both with respect to performance as well as from manufacturing complexity. In addition, some prior art solutions are limited to a relatively small dose of API, because of the amount of space occupied by other components of the dosage form. Many of the dosage forms have also been limited as far as not being able to provide an arbitrary release profile, but rather have been essentially designed around one very specific release profile with little ability to adjust that release profile.
Accordingly, it would be desirable to provide dosage forms, such as erosion-based dosage forms, capable of providing zero-order release, and also, in general, capable of providing any desired release profile such as escalating release or decreasing release. It would also be desirable to provide associated methods of manufacture. It would also be desirable to provide a generalized methodology for designing such dosage forms that allows the desired release profile to be achieved with a minimum amount of trial-and-error iteration of designs of dosage forms.